Gating of Voltage-Dependent K+ Channels (more . . .)
+
of Voltage-Dependent
(more . .activation
.)
WeGating
are investigating
the mechanismKofChannels
voltage-dependent
in K+
+
We are investigating
thetetramers
mechanism
of voltage-dependent
activation
channels.
K+ channels are
with
a central K+-selective
pore andin4K
channels.
K+ channels
withUpon
a central
K+-selective
pore and 4
voltage
sensor
domains, are
onetetramers
per subunit.
membrane
depolarization,
voltage
domains,
per +subunit.
Upon membrane
depolarization,
changes
the
voltage
sensor
domainsone
undergo
conformational
result in
Gating
ofsensor
Voltage-Dependent
K Channels
(more
. . .) that
the
voltage
sensor
domains
undergo
conformational
changes
that
result+ in
poreare
opening.
Our current
goals areoftovoltage-dependent
identify experimental
constraints
We
investigating
the mechanism
activation
in K
pore
opening.
Our current
goals
are
to identify
experimental
constraints
+
+
that
make
it
possible
to
model
the
structure
of
the
closed
channel
and
channels. K channels are tetramers with a central K -selective pore andto
4
that makethe
it possible
to taken
model by
the the
structure
of the closed
channel
and to
determine
pathway
S4
segment,
the
main
moving
voltage sensor domains, one per subunit. Upon membrane depolarization,
determine
the
pathway
taken
byactivation.
the S4 segment, the main moving
element
in the
voltage
sensor,
during
the
voltage
sensor
domains
undergo
conformational changes that result in
element in the voltage sensor, during activation.
pore opening. Our current goals are to identify experimental constraints
that make it possible to model the structure of the closed channel and to
determine the pathway taken by the S4 segment, the main moving
elementGating
in the voltage
sensor, during activation.
of Voltage-Dependent
K+ Channels (more . . .)
We are investigating the mechanism of voltage-dependent activation in K+
channels. K+ channels are tetramers with a central K+-selective pore and 4
voltage sensor domains, one per subunit. Upon membrane depolarization,
the voltage sensor domains undergo conformational changes that result in
pore opening. Our current goals are to identify experimental constraints
that make it possible to model the structure of the closed channel and to
determine the pathway taken by the S4 segment, the main moving
element in the voltage sensor, during activation.
Neuronal Excitability and Spinocerebellar Ataxia Type 13 (more . . .)
Spinocerebellar Ataxia Type 13 is an autosomal dominant genetic disease in humans caused by
mutations in KCNC3, which encodes Kv3.3, a voltage-gated K+ channel. The two original SCA13
mutations are associated with distinct clinical manifestations. A mutation in the voltage sensor domain
leads to progressive, adult-onset ataxia accompanied by degeneration of cerebellar neurons. This
mutant subunit has a strong dominant negative effect on Kv3 expression. In contrast, a mutation in the
pore domain causes a form of SCA13 that emerges in infancy, characterized by a severely shrunken and
malformed cerebellum and non-progressive motor deficits. This mutation affects gating, shifting the
voltage dependence of activation in the negative direction and dramatically slowing channel closing.
We are testing the hypothesis that changes in Kv3.3 channel function alter the excitability of cerebellar
neurons, with detrimental consequences for motor behavior and neuronal survival during brain
development or aging. We are working to determine how changes in excitability decrease the viability
of neurons and why different mutations affect neuronal survival at different stages of life.
Gating of Voltage-Dependent K+ Channels (more . . .)
We are investigating the mechanism of voltage-dependent activation in K+
channels. K+ channels are tetramers with a central K+-selective pore and 4
voltage sensor domains, one per subunit. Upon membrane depolarization,
the voltage sensor domains undergo conformational changes that result in
pore opening. Our current goals are to identify experimental constraints
that make it possible to model the structure of the closed channel and to
determine the pathway taken by the S4 segment, the main moving
element in the voltage sensor, during activation.
Neuronal Excitability & Spinocerebellar Ataxia Type 13 (more . . .)
Spinocerebellar Ataxia Type 13 is an autosomal dominant genetic disease in
humans caused by mutations in KCNC3, which encodes Kv3.3, a voltagegated K+ channel. The two original SCA13 mutations are associated with
distinct clinical manifestations. A mutation in the voltage sensor domain
leads to progressive, adult-onset ataxia accompanied by degeneration of
cerebellar neurons. This mutant subunit has a strong dominant negative
effect on Kv3 expression. In contrast, a mutation in the pore domain causes
a form of SCA13 that emerges in infancy, characterized by a severely
shrunken and malformed cerebellum and non-progressive motor deficits.
This mutation affects gating, shifting the voltage dependence of activation
in the negative direction and dramatically slowing channel closing. We are
testing the hypothesis that changes in Kv3.3 channel function alter the
excitability of cerebellar neurons, with detrimental consequences for motor
behavior and neuronal survival during brain development or aging. We are
working to determine how changes in excitability decrease the viability of
neurons and why different mutations affect neuronal survival at different
stages
of life.
Zebrafish
Model of Human Ataxia (more . . .)
We are expressing SCA13 mutant subunits in zebrafish to determine the
consequences for neuronal function, development, viability, and locomotor
behavior. Currently, we are focusing on spinal cord neurons. Endogenous
Kv3.3 is expressed in motor neurons that control the fastest and largest
amplitude movements in zebrafish, including the startle (escape) response.
We are investigating the effects of a SCA13 dominant negative subunit on
the excitability of these neurons and on the kinematic parameters of the
startle response.